Non-oncologic incidental uptake on FAPI PET/CT imaging

Abstract

Fibroblast-activation protein (FAP) is a serine protease classified in the dipeptidyl peptidase 4 (DPP4) family. FAP is predominantly expressed in activated fibroblasts such as the cancer-associated fibroblasts (CAFs). FAP expression in CAFs is associated with tumor progression and poor prognosis in solid cancers. Recently, radiolabeled FAP inhibitors (FAPI) has been developed, which enables positron emission tomography (PET) imaging of FAP. FAPI PET/ computed tomography (CT) can provide a higher tumor-to-background ratio (TBR) than 18F-fluorodeoxyglucose (FDG) PET/CT in various cancers, and thus has attracted substantial attention. As studies on FAPI PET grow in number and size, incidental findings related to non-oncologic conditions have been increasingly reported. FAPI PET uptake has been reported in various conditions such as benign tumors, fibrotic, granulomatosis, scarring/wound, degenerative diseases, and inflammatory diseases. The knowledge of physiological and non-oncologic causes of FAPI uptake is indispensable for accurate FAPI PET/CT interpretation and can help appropriate management of incidental findings on FAPI PET/CT in patients referred for cancer staging indications. In this review article, we describe for each organ system (Brain, Oral mucosa, Salivary Glands, Thyroid, Lung, Myocardium, Breast, Esophagus, Stomach, Intestine, Liver, Gallbladder, Pancreas, Spleen, Kidney, , Uterus, Bone marrow, Joints, Muscle, Vessels, Lymph nodes) the patterns of physiological FAPI uptake and the main causes of non-oncological uptake reported from the literature with FAPI-02, FAPI-04 and FAPI-46. We also illustrate some examples from our institutional database at UCLA.

Subclass Analysis of Malignant, Inflammatory and Degenerative Pathologies Based on Multiple Timepoint FAPI-PET Acquisitions Using FAPI-02, FAPI-46 and FAPI-74

“…According to that, many non-malignant pathologies, such as IgG4-related disease, pulmonary and renal fibrosis, liver cirrhosis and arthritis, show marked tracer uptake in FAPI-PET [ 11 , 12 , 13 , 14 , 15 ]. The differentiation of malignant from non-malignant FAPI-PET positive lesions still makes the interpretation of FAPI-PET scans challenging [ 16 , 17 ]. To date, only few studies have analyzed potential differences of FAPI-uptake between malignant and non-malignant lesions [ 11 , 17 , 18 ].…”

“…The differentiation of malignant from non-malignant FAPI-PET positive lesions still makes the interpretation of FAPI-PET scans challenging [ 16 , 17 ]. To date, only few studies have analyzed potential differences of FAPI-uptake between malignant and non-malignant lesions [ 11 , 17 , 18 ]. Subclasses of malignant lesions (primary tumors, local recurrences, and different forms of metastases) have been analyzed for single time point FAPI-PET imaging (e.g., [ 19 , 20 ]), but potential differences in FAPI-PET of subclasses of non-malignant tissues have not yet been described.…”

Emerging Role of FAPI PET Imaging for the Assessment of Benign Bone and Joint Diseases

“…In this setting, fibroblast activation protein (FAP) inhibitors (FAPI), labelled with both 18 F or 68 Ga, are emerging as promising radiopharmaceuticals. FAPI are molecules able to bind to FAP, a membrane serine protease that is highly expressed on activated fibroblasts present in a wide range of pathophysiological conditions, such as wound-healing, inflammation and cancer [ 10 , 11 , 12 ]. In this scenario, the role of FAPI PET/CT for the evaluation of cancer has been evaluated in several studies and the preliminary results are promising, as it also seems to allow the evaluation of tumors with low [ 18 F]FDG uptake.…”

“…However, on the other side, some authors hypothesized a different mechanism of uptake, related to the increased vascularity and capillary permeability due to inflammatory response, resulting in high perfusion and blood-pool effects [ 20 ]. Nevertheless, one of the advantages of the use of FAPI imaging for the assessment of bone lesions is the fact that bone marrow usually exhibits low physiological FAPI uptake [ 12 , 18 ].…”

“…Several case reports have reported that radiolabeled FAPI uptake is associated with a high number of benign conditions that affect the bones and the joints, such as fibrous dysplasia [ 22 ], tuberculosis [ 23 ], osteoarthritis, enthesopathies, myositis ossificans [ 24 ], Erdheim–Chester disease [ 25 ], ankylosing spondylitis [ 26 ], fractures [ 20 ], synovitis, osteitis and rheumatoid arthritis (RA) [ 12 ]. In particular, arthritis is generally underlined as an incidental finding at radiolabeled FAPI PET/CT and the most common sites of uptake are facet, shoulder, sternoclavicular joints and knees [ 11 , 20 , 27 , 28 , 29 ].…”